Activatable Small-Molecule Hydrogen Sulfide Donors

Abstract

Significance: Hydrogen sulfide (H₂S) is an important biological signaling molecule involved in many physiological processes. These diverse roles have led researchers to develop contemporary methods to deliver H₂S under physiologically relevant conditions and in response to various stimuli. Recent Advances: Different small-molecule donors have been developed that release H₂S under various conditions. Key examples include donors activated in response to hydrolysis, to endogenous species, such as thiols, reactive oxygen species, and enzymes, and to external stimuli, such as photoactivation and bio-orthogonal chemistry. In addition, an alternative approach to release H₂S has utilized the catalyzed hydrolysis of carbonyl sulfide (COS) by carbonic anhydrase to generate libraries of activatable COS-based H₂S donors. Critical Issues: Small-molecule H₂S donors provide important research and pharmacological tools to perturb H₂S levels. Key needs, both in the development and in the use of such donors, include access to new donors that respond to specific stimuli as well as donors with well-defined control compounds that allow for clear delineation of the impact of H₂S delivery from other donor byproducts. Future Directions: The abundance of reported small-molecule H₂S donors provides biologists and physiologists with a chemical toolbox to ask key biological questions and to develop H₂S-related therapeutic interventions. Further investigation into different releasing efficiencies in biological contexts and a clear understanding of biological responses to donors that release H₂S gradually (e.g., hours to days) versus donors that generate H₂S quickly (e.g., seconds to minutes) is needed.

Keywords: carbonyl sulfide; hydrogen sulfide; reactive sulfur species; small molecule donors.

FIG. 1.

Selected roles of H₂S in major organ systems. H₂S, hydrogen sulfide; NSAID, nonsteroidal anti-inflammatory drug. Color images are available online.

FIG. 2.

General classes of H₂S release from small-molecule donors. Color images are available online.

FIG. 3.

Enzyme-activated donors and associated enzymes. (a) Structures of enzymatically triggered COS and H₂S donors. (b) Structures of PLE and Escherichia coli NTR. COS, carbonyl sulfide; NTR, nitroreductase; PLE, porcine liver esterase. Color images are available online.

FIG. 4.

H₂O₂-triggered COS donor scaffolds. H₂O₂, hydrogen peroxide.

FIG. 5.

Hydrolysis-activated H₂S donors. The pH windows shown represent specific pH values or pH windows in which H₂S release was reported or in which H₂S release was reported to be optimal. Color images are available online.

FIG. 6.

Structures of donor compounds activated in the presence of biological thiols. (a) H₂S donors activated in the presence of cysteine. (b) H₂S donors activated in the presence of cysteine and GSH. GSH, glutathione. Color images are available online.

FIG. 7.

Structures and excitation wavelengths of selected photoactivable H₂S donors. PS indicates photosensitizer. IR, infrared; UV, ultraviolet. Color images are available online.

FIG. 8.

Structures of COS-based donor compounds activated by miscellaneous activators. (a) H₂S-activated analyte replacement probe. (b) “Click and release” bio-orthogonal COS-based H₂S donor. (c) Activation of N-thiocarboxyanhydride by glycine to generate H₂S. Color images are available online.